What

There are several types of human papillomavirus (HPV) that infect cutaneous and mucosal epithelial tissues. Most people clear HPV infections, but the virus persists in some cases.

Who

9vHPV (9-valent HPV) vaccine is recommended for:

adolescents aged 9–18 years

people with significant immunocompromising conditions (except for asplenia or hyposplenia)

men who have sex with men

How

The recommended schedule for adolescents aged 9–14 years is 2 doses, with a 6–12-month interval between doses.

The recommended schedule for people aged ≥15 years is 3 doses, with an interval of 2 months between dose 1 and dose 2, and 4 months between dose 2 and dose 3.

The recommended schedule for people with significant immunocompromising conditions, regardless of age, is 3 doses, with an interval of 2 months between dose 1 and dose 2, and 4 months between dose 2 and dose 3.

Why

Up to 90% of the general population will be infected with at least 1 genital type of HPV at some time in their lives. People with persistent HPV infection are at risk of developing HPV-associated cancers; the most common is cervical cancer.

Adolescents

The recommended schedule for adolescents aged 9–14 years is 2 doses, with a 6–12-month interval between doses.1-5

The recommended schedule for adolescents aged 15–18 years (that is, past their 15th birthday) at the time of their 1st HPV vaccine is 3 doses, with an interval of 2 months between dose 1 and dose 2, and 4 months between dose 2 and dose 3.

Patterns of male HPV infection are markedly different from those of women. Men have stable incidence and prevalence throughout life. Most women develop effective immunity early in the years after sexual debut.8,9

Overall, MSM have a higher risk of repeated and persistent HPV infection and associated diseases, such as genital warts and anal cancer. This is regardless of their HIV status or other immunocompromising conditions.6,10 In addition, at the population level, MSM are less likely to benefit from herd protection attained from HPV vaccination of females.

Cervical screening and HPV vaccination

Women who have received HPV vaccine are recommended to undergo cervical screening according to current guidelines.11

Vaccination is a preventive measure, complementary to cervical screening, and vice versa. HPV types other than those included in the current vaccines can cause cervical cancer. Therefore, both cervical screening and HPV vaccination are recommended.

Women aged 25–70 years are recommended to have HPV testing every 5 years, with exit testing at 70–74 years.

For women who have recently been diagnosed with cervical dysplasia or HPV infection, or have been treated for this in the past, HPV vaccine will not affect current disease. However, HPV vaccination may be warranted, because it can prevent:12

Table. Recommended doses and intervals between doses for human papillomavirus (HPV) vaccines, by age group at the start of the course

Age group

Recommended doses

Recommended schedule

Notes

Starting HPV vaccination at 9–14 years of age (except people who are immunocompromised)

2

0, 6–12 months

The recommended age for HPV vaccination is 12–13 years, but people can receive vaccines from 9 years of age.

If a person has received 2 doses of HPV vaccine with an interval of <5 months between dose 1 and dose 2, they need a 3rd dose at least 12 weeks after the 2nd dose. Ensure that the minimum intervals for 3 doses are met.

If the 2nd dose is received <6 months but ≥5 months after the 1st dose, a 3rd dose is not required; clinical trial data support this interval still being sufficiently immunogenic.

Starting HPV vaccination at ≥15 years of age

3

0, 2, 6 months

A 3-dose schedule of 0, 1 and 6 months for 2vHPV (2-valent HPV) vaccine is acceptable.

People who are immunocompromised at any age (excluding those with asplenia or hyposplenia)

3

0, 2, 6 months

A 3-dose schedule of 0, 1 and 6 months for 2vHPV vaccine is acceptable.

Extra doses of 9vHPV vaccine

People who have completed the recommended number of doses of 2vHPV (2-valent HPV) or 4vHPV (4-valent HPV) vaccine are not routinely recommended to receive 9vHPV vaccine, because the extra benefit is thought to be marginal.

However, if the person wants protection against the additional HPV types, there appears to be no safety concerns associated with giving 9vHPV after a completed 2vHPV or 4vHPV course. 13 The rate of injection site reactions may increase.

Co-administration with other vaccines

HPV vaccines can be given at the same time as the following vaccines, using separate syringes and injection sites:14-20

There are no clinical data about co-administering HPV vaccines with varicella vaccine. Theoretically, there are no concerns about safety or efficacy if the person receives the vaccines at the same time at different injection sites.

Interchangeability of HPV vaccines

9vHPV vaccine can be used to complete an HPV vaccination schedule that was started with either the 4vHPV or the 2vHPV vaccine, as long as the appropriate minimum intervals and dose numbers are used.

Women who are pregnant or breastfeeding

Women who become pregnant after starting the HPV vaccination course are recommended to stop the vaccination course and receive the remaining doses after pregnancy.

Women who are inadvertently given a dose of HPV vaccine around the time of conception or during pregnancy should be told that there is a large body of evidence suggesting that vaccination does not harm the mother or the fetus in these situations.

In the 9vHPV vaccine clinical trials, some women became pregnant during the trial, despite recommendations for participants to avoid pregnancy. The overall proportions of pregnancies that resulted in an adverse outcome (spontaneous abortion, late fetal death, infant with congenital anomalies) were similar among 9vHPV vaccine recipients and placebo or control vaccine recipients.21 In addition, pooled analyses of women who became pregnant during clinical trials of 2vHPV and 4vHPV vaccines showed that, overall, there were no differences in pregnancy outcomes between HPV vaccine recipients and control vaccine recipients.22-24

HPV vaccination is generally safe and well tolerated. The safety profile and the spectrum of adverse events after vaccination in males are similar to those in females.26,27

For all HPV vaccines, injection site reactions are the most commonly reported adverse event.21,28,29

In most clinical trials, systemic adverse events were comparable between HPV vaccine recipients and control vaccine recipients, and included:29,30

headache

fever

nausea

dizziness

fatigue

Meta-analyses on both the 2vHPV and 9vHPV vaccines show no increase in the number of serious adverse events in vaccine recipients compared with control recipients.21,31 Rates of anaphylaxis are low and consistent with rates for other vaccines.28,32,33

Adverse events following 9vHPV compared with 4vHPV

A safety review of 7 phase III clinical trials evaluated reactions to 9vHPV vaccine and compared them with 4vHPV vaccine or placebo in males and females aged 9–26 years who received 3 doses. Serious adverse reactions were reported in <0.1% of the more than 15,000 participants.21 This review concluded that overall safety profiles of the 4vHPV and 9vHPV vaccines given in 3-dose schedules were similar, but found that injection site reactions were slightly more common with 9vHPV vaccine (72.5% after dose 1 of 9vHPV vaccine vs 61.0% after dose 1 of 4vHPV vaccine).

Syncope in adolescents

Post-marketing passive surveillance of HPV vaccine use has identified syncope (fainting) as a common adverse event immediately after HPV vaccination in adolescents.28,34,36

Syncope is a benign and manageable risk of adolescent vaccination. It is likely to be a reaction to the process of vaccination, rather than to the vaccine itself. Immunisation providers should ensure that procedures are in place to minimise the risk of syncope-related falls around the time of vaccination.

Guillain–Barré syndrome

A 2015 French study in more than 2 million girls suggested a possible very small risk (approximately 1 in 100,000 girls vaccinated) of Guillain–Barré syndrome (GBS). However, a relationship between HPV vaccination and GBS has not been observed in any other well-conducted studies.37 Ongoing research is monitoring whether there is any increased risk of GBS after HPV vaccination.

Other adverse events

Reports of various other adverse events after HPV vaccination include:

new-onset autoimmune disease

primary ovarian insufficiency

complex regional pain syndrome

postural orthostatic tachycardia

Despite these reports, there is no consistent evidence for an increased risk of these events after vaccination, or a causal relationship between these events and vaccination.28,33

The World Health Organization’s Global Advisory Committee on Vaccine Safety,38 the European Medicines Agency,39 the Australian Therapeutic Goods Administration and various other key global expert vaccine groups have reviewed the evidence for a causal association between HPV vaccine and a number of these reported adverse events. These extensive reviews have not found any safety issue that would change positive recommendations for the use of the vaccine. The reviews have concluded that HPV vaccines are extremely safe.37

More than 100 HPV genotypes have been fully sequenced. The genotypes are differentiated by sequence variations in the major genes. HPV genotypes differ in their preferred site of infection. Approximately 40 HPV types specifically infect the anogenital tract.40

Pathogenesis

HPV requires a breach in the epithelial surface to enter the basal epithelial cells and cause infection. However, infectious virions are only produced in the terminally differentiated layer of the epithelium.41

HPV types 16, 18, 31, 33, 35, 45, 52 and 58 are high risk because they can cause cancer. The most oncogenic HPV type is HPV-16. This is the most frequent cause of HPV-related cancers. See Clinical features.42

HPV types 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 and 89 are low risk. These are mostly associated with non-malignant lesions such as genital warts. Other HPV types are uncommon, and their associations with disease are undetermined. However, they are not currently believed to be significant causes of cancer.43,44

Transmission

Anogenital HPV is mainly transmitted through sex. Less commonly, the virus can be transmitted after intimate non-penetrative sexual contact.45

Perinatal transmission of HPV can result in laryngeal infection in infants. In rare cases, this can lead to recurrent respiratory papillomatosis.46

HPV infection is often subclinical, but can cause a range of lesions depending on the infecting HPV genotype.

Low-risk HPV types

Low-risk HPV types may cause lesions such as:

cutaneous warts

genital warts

respiratory papillomatosis

Anogenital warts may present as painless lumps, or with local tenderness, itching or bleeding.

Recurrent respiratory papillomatosis is potentially fatal. It is characterised by multiple warty growths on the mucosal surface of the respiratory tract.47

Most people clear genital HPV infections (that is, the infection is no longer detectable by HPV DNA testing) within 12–24 months. However, in some cases, the virus is thought to remain as a latent infection even though DNA is no longer detectable.

In about 3–10% of infections, the virus persists. People with persistent HPV infection are at risk of developing HPV-associated cancers.48-50

High-risk HPV types

High-risk HPV types may cause dysplasias and cancers of the:

cervix

vulva

vagina

penis

anus

oral cavity

oropharynx

Dysplasias may be:

low grade — the viral cytopathic effect of HPV infection

high grade — precursors to cancer

Cervical cancer

The causal link between persistent cervical HPV infection and cervical cancer is well established.51

Cellular changes in the cervix as a result of HPV infection are referred to as cervical intraepithelial neoplasia. Most of these changes regress, but some will progress to cervical cancer.

Malignant transformation in the cervix usually occurs 10–20 years after infection with high-risk HPV types, but has been reported within 2 years.52

Other cancers

The strength of association between HPV infection and cancers other than cervical cancer varies by site and HPV type.51

The clinical features of HPV-associated cancers and their precursor lesions depend on the anatomical site. Clinical features also vary within the oropharynx and anogenital sites other than the cervix. The progression of HPV-associated precursor lesions to cancers is less well understood in non-cervical sites than in the cervix.

Infection with HPV is very common in both men and women. Initial infection occurs close to the time of sexual debut. Up to 90% of the general population will be infected with at least 1 genital type of HPV at some time in their lives.53

The median age of sexual debut for both males and females in Australia was 17 years in 2012–13.54 In 2008, a national survey found that about 80% of senior secondary school children aged approximately 15–19 years engaged in some form of sexual activity that may transmit HPV.55

Having more sexual partners is associated with an increased risk of acquiring HPV.56

HPV infection rates differ between geographic regions. Estimated population prevalence of HPV also varies depending on the anatomical site and the lesions sampled.

About two-thirds of Australian women aged 15–20 years participating in cervical screening had HPV DNA detected in cervical samples collected for cytology.57

Less than 60% of women with HPV infection develop antibodies. The proportion is even lower in men.58-60 In a 2005 Australian serosurvey, 24% of females and 18% of males aged 0–69 years were seropositive to at least 1 of the 4 HPV types 6, 11, 16 and 18.61 Females became seropositive to HPV at 10–14 years of age and males at 15–19 years of age.

Risk groups

Certain population subgroups are at increased risk of HPV infection and HPV-associated diseases than the general population:

Men who have sex with men (MSM) are more commonly infected with multiple HPV genotypes and take longer to clear infection.6,62,63

MSM who are also HIV-positive have a higher prevalence of high-risk HPV types than MSM who are HIV-negative.6

People who are immunocompromised (as a result of disease or medical treatment) are at increased risk of HPV-related disease.56

Diseases attributed to HPV infection

Cervical cancer

Prevalence of HPV-16 and HPV-18 in Australia

Australian data collected between 2005 and 2015 indicate that HPV-16 and HPV-18 are detected in approximately 77% of all cervical cancers. It is estimated that an extra 15.9% of cervical cancers are attributable to HPV types 31, 33, 45, 52 and 58.65-67

In Australia, cervical cancer ranked 23rd of cancers contributing to the overall cancer disease burden in 2011. Cervical cancer occurs predominantly in women who are unscreened or underscreened through the National Cervical Screening Program.68

Incidence and prevalence of cervical cancer

In 2014, the age-standardised incidence rate of cervical cancer in Australia was 6.8 per 100,000. The mortality rate was 1.7 deaths per 100,000 women.69

The prevalence of high-risk HPV types 16 and 18, detected when cervical samples collected for cytology were tested for HPV DNA, was similar in Aboriginal and Torres Strait Islander women and non-Indigenous women.57

However, the incidence rate of cervical cancer in Aboriginal and Torres Strait Islander women is more than 2 times that in non-Indigenous Australian women. This indicates that fewer Aboriginal and Torres Strait Islander women participate in cervical screening programs. It also suggests a greater prevalence of cofactors for cervical cancer, such as:69,70

smoking

earlier and more pregnancies

lower socioeconomic status

Aboriginal and Torres Strait Islander women are 4 times more likely to die from cervical cancer than non-Indigenous women.69

Australian women in remote and very remote areas have 1.5 times higher cervical cancer incidence than those living in major cities.69

Surveillance data have shown a positive impact of the HPV vaccination program on cervical intraepithelial neoplasia.71 Victorian data show a 48% decline in the incidence of high-grade cervical abnormalities in girls aged <18 years within 4 years of the start of the National HPV Vaccination Program.71 More recent Victorian and national cervical screening data demonstrate a decline in high-grade lesions in women aged up to 30 years.69,72

Other anogenital cancers

Proportion attributed to HPV

The proportion of cancers of anogenital sites other than the cervix that are attributable to HPV ranges from approximately 40% for vulval cancers to approximately 85% for anal cancers.

Of these HPV-associated cancers:

more than 85% have evidence of infection with the high-risk HPV types 16 and 1873-78

about 11–18% in women and 4–9% in men are attributable to HPV types 31, 33, 45, 52 and 5879

Incidence of anogenital cancers

In Australia in 2013, the incidence of:80

vulval cancer was 2.5 per 100,000 (n = 341)

vaginal cancer was 0.6 per 100,000 (n = 83)

penile cancer was 0.9 per 100,000 (n = 104)

anal cancer was 1.5 per 100,000, with a slightly higher incidence in females than in males (age-standardised)

MSM have a significantly higher incidence of high-grade anal intraepithelial neoplasia and anal cancer than the general population. Overseas studies have found a greater than 30-fold higher incidence of anal cancer in MSM than in other men.10,81

Overall, anal cancer incidence has been steadily increasing during the past few decades. The increase has been greater in males than in females.73,76

Oropharyngeal cancers

The proportion of oropharyngeal cancers that are associated with HPV varies widely, from 12% to 63%. The proportion of oral cancers associated with HPV is lower.82-84 HPV-16 and HPV-18 account for more than 85% of HPV-positive cancers at these sites.

Many western countries, including Australia and the United States, have seen a steady increase in the burden of HPV-positive oropharyngeal cancers during the past few decades.73,82,85-88 These cancers are mainly attributable to cancers of the base of the tongue and tonsils.

HPV-associated lesions

The population incidence of benign HPV-associated lesions, such as anogenital warts, is much higher than the incidence of HPV-associated cancers.

In Australia, the estimated annual incidence of anogenital warts in 2000–06 (before the HPV vaccine was introduced in 2007) was 206 per 100,000 in males and 231 per 100,000 in females. The highest incidence was in the 25–29-year age group for men (rate 740 per 100,000) and the 20–24-year age group for women (rate 861 per 100,000).89 4.0% of men and 4.4% of women aged 16–59 years reported ever being diagnosed with genital warts.90

The estimated cumulative lifetime risk of genital warts is 10%.91,92 The estimated incidence of anogenital warts in MSM is about 10 times higher than in the general population. About 33% of HIV-negative MSM report a history of these lesions.89,93

HPV types 6 and 11 are associated with 90% of genital warts.94-96

HPV vaccination will take decades to affect cancer incidence. However, surveillance data show a large impact on the incidence of genital warts97,98 after the female vaccination program was introduced.

A study including 8 sexual health centres showed a 59% decrease in the proportion of vaccine-eligible female first-time clinic attendees diagnosed with genital warts.99 Vaccinating females also provides some herd protection to males — there was a significant decline in the diagnosis of genital warts in unvaccinated males of the same age.99-101

Respiratory papillomatosis

Recurrent respiratory papillomatosis is a rare disease (prevalence approximately 3.5 per 100,000) that occurs in both childhood and adult forms. It is associated with HPV types 6 and 11 in 100% of cases.95,102-104

Virus-like particles are not infectious, and do not replicate or cause cellular abnormalities.105,106

From 2007 to 2017, Australia’s National Immunisation Program used 4vHPV. This was replaced with 9vHPV from 2018.

Vaccine efficacy in females 16–26 years of age

Efficacy of the 2vHPV, 4vHPV and 9vHPV vaccines has been assessed in females in several international clinical trials.

2vHPV and 4vHPV vaccines

In women aged approximately 16–26 years who are naive to HPV types 16 and 18 before vaccination, the 2vHPV and 4vHPV vaccines (in a 3-dose schedule) are both about 90–100% effective at preventing type-specific persistent infection and related cervical disease.

9vHPV vaccine

The 9vHPV vaccine has established efficacy (97.4%; 95% CI: 85.0–99.9%) against the following neoplasias and cancers that are associated with HPV types 31, 33, 45, 52 and 58:114

cervical

vulval

vaginal

A clinical trial of 9vHPV vaccine in women aged 16–26 years established non-inferiority of the 9vHPV vaccine against the 4vHPV types (6, 11, 16 and 18). Incidence of disease endpoints was similarly low in women vaccinated with either 9vHPV or 4vHPV vaccine.114

Vaccine efficacy in males 16–26 years of age

Vaccination was 84–100% protective against persistent anogenital infection and external genital lesions due to vaccine HPV types among HPV-naive participants.

Among HPV-naive participants in the trial, vaccine efficacy in men who have sex with men was:

95% against intra-anal HPV infection

75% against high-grade anal intraepithelial neoplasia

Efficacy of 2vHPV and 9vHPV vaccines in males has not been assessed to date. However, these vaccines have demonstrated safety and immunogenicity in adolescent and adult males.27,27,116

Vaccine efficacy in people already infected with HPV

In women who are vaccinated regardless of their baseline HPV status (that is, women who may have pre-existing HPV infection), vaccine efficacy is lower than in HPV-naive women. This suggests reduced vaccine effectiveness among females who are already sexually active. This is because the HPV vaccines are prophylactic vaccines — they prevent primary HPV infection.

Vaccination does not:

treat an existing HPV infection

prevent disease that may be caused by an existing vaccine HPV-type infection30,117-119

HPV vaccine protection is believed to be predominantly antibody mediated. Even low levels of antibodies can stop HPV entering the basal epithelial cells. HPV can only access the basal cell at sites of microtrauma, where there is a breach in the epithelium, and circulating HPV antibodies from sera are present at these sites.41

Because antibodies prevent viral entry, vaccination may still benefit sexually active men and women by protecting them against:

new infections with other vaccine-preventable HPV types

reinfection with vaccine-preventable types they have previously been exposed to — for example, from an infected partner

auto-inoculation of existing persistent HPV infection to other sites

Immunogenicity in females and males <16 years of age

Pre-market trials did not assess the efficacy of HPV vaccines in females or males <16 years of age because these studies need genital samples. The trials used immunobridging studies to ensure that antibody responses in the target age of young adolescents were equivalent to those known to be protective in older women.

Young adolescents had higher antibody titres than older women.1 Later studies confirmed that a widely spaced 2-dose HPV vaccine schedule for those aged 9–14 years at the time of the 1st dose also produced non-inferior antibody titres.120

For the 2vHPV, 4vHPV and 9vHPV vaccines, antibody responses in pre-adolescent and adolescent females and males (>9 years of age) after 2 vaccine doses were equivalent to those in adult women, in whom clinical efficacy has been demonstrated.1,2,121

Duration of immunity

It is currently unknown if immunity due to HPV vaccine is lifelong. However, current data support a persistent, stable antibody level after an initial plateau. Long-term population-based follow-up studies to assess this are underway. In clinical trials in women,114,122-124 vaccine efficacy is up to:

Brotherton JM, Wrede CD. Offering HPV vaccination to women treated for high-grade cervical intra-epithelial neoplasia: what do you need to know? [letter]. Australian and New Zealand Journal of Obstetrics and Gynaecology 2014;54:393-4.

Garland SM, Cheung TH, McNeill S, et al. Safety and immunogenicity of a 9-valent HPV vaccine in females 12–26 years of age who previously received the quadrivalent HPV vaccine. Vaccine 2015;33:6855-64.

Adelstein DJ, Ridge JA, Gillison ML, et al. Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9–10, 2008, Washington, DC. Head and Neck 2009;31:1393-422.

Grulich AE, de Visser RO, Smith AM, Rissel CE, Richters J. Sex in Australia: sexually transmissible infection and blood-borne virus history in a representative sample of adults. Australian and New Zealand Journal of Public Health 2003;27:234-41.